Project Summary Injuries or diseases that kill retinal neurons or photoreceptors block vision at it source. The inability to repair the retina is a hallmark of the human nervous system; neurons that die are not replaced and functions that are lost are not recovered. This bleak outcome is a driving force for research on neural stem cells and the field of regeneration biology. The long-term objective of this project is to elucidate the molecular mechanisms that regulate the birth, death and regeneration of neurons and photoreceptors in the vertebrate retina. This program of research utilizes the zebrafish retina, the only vertebrate CNS tissue in which intrinsic stem cells can regenerate a single neuronal type that integrates into existing synaptic circuits or regenerate all cell types that completely restore the original tissue. Investigating stem cell-based developmental and regenerative neurogenesis will advance our knowledge of the mechanisms that govern retinal stem and progenitor cells and will guide the therpeutic use of stem and progenitor cells to treat retinal injuries, blindness and disease. Three Specific Aims are proposed, each directed toward revealing mechanisms that regulate the genesis and regeneration of retinal neurons and photoreceptors. Specific Aim 1 will test the hypothesis that photoreceptor genesis is governed through post-transcriptional regulation of NeuroD by the the microRNA, miR-18a. Specific Aim 2 will determine the combined and independent functions of the Midkine paralogs during retinal development and photoreceptor regeneration. Specific aim 3 will test the hypothesis that the matrix metalloproteinase, MMP9, is induced in Mller glia by TNF-?, and together these molecules are components of an acute inflammatory response that governs photoreceptor regeneration. Together these specific aims represent a focused and integrated research program to test specific hypotheses about the biology and regulation of developmental neurogenesis and adult photoreceptor regeneration in the vertebrate retina. This program of research will expand our knowledge of photoreceptor death and regeneration and the molecular mechanisms that regulate retinal stem and progenitor cells. These studies also will have implications for the NEI Audacious Goals Initiatives.